chr6-45474713-T-C

Variant names:

• chr6-45474713-T-C
• rs2790098
• NM_001024630.4:c.686-17228T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001024630.4(RUNX2):​c.686-17228T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.268 in 152,034 control chromosomes in the GnomAD database, including 6,138 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.27 (6138 hom., cov: 31)
• Consequence: RUNX2 NM_001024630.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.109
• Publications: 5 publications found

Genes affected

RUNX2 (HGNC:10472): (RUNX family transcription factor 2) This gene is a member of the RUNX family of transcription factors and encodes a nuclear protein with an Runt DNA-binding domain. This protein is essential for osteoblastic differentiation and skeletal morphogenesis and acts as a scaffold for nucleic acids and regulatory factors involved in skeletal gene expression. The protein can bind DNA both as a monomer or, with more affinity, as a subunit of a heterodimeric complex. Two regions of potential trinucleotide repeat expansions are present in the N-terminal region of the encoded protein, and these and other mutations in this gene have been associated with the bone development disorder cleidocranial dysplasia (CCD). Transcript variants that encode different protein isoforms result from the use of alternate promoters as well as alternate splicing. [provided by RefSeq, Jul 2016]

RUNX2 Gene-Disease associations (from GenCC):

• cleidocranial dysplasia 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• metaphyseal dysplasia-maxillary hypoplasia-brachydacty syndrome

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.338 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RUNX2	NM_001024630.4	c.686-17228T>C		intron_variant	Intron 5 of 8	ENST00000647337.2	NP_001019801.3
RUNX2	NM_001369405.1	c.644-17228T>C		intron_variant	Intron 3 of 6		NP_001356334.1
RUNX2	NM_001015051.4	c.686-17228T>C		intron_variant	Intron 5 of 7		NP_001015051.3
RUNX2	NM_001278478.2	c.644-17228T>C		intron_variant	Intron 3 of 5		NP_001265407.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RUNX2	ENST00000647337.2	c.686-17228T>C		intron_variant	Intron 5 of 8		NM_001024630.4	ENSP00000495497.1

Frequencies

GnomAD3 genomes AF: 0.269 AC: 40827 AN: 151918 Hom.: 6140 Cov.: 31

Gnomad AFR AF: 0.150

Gnomad AMI AF: 0.209

Gnomad AMR AF: 0.288

Gnomad ASJ AF: 0.396

Gnomad EAS AF: 0.0443

Gnomad SAS AF: 0.268

Gnomad FIN AF: 0.310

Gnomad MID AF: 0.231

Gnomad NFE AF: 0.342

Gnomad OTH AF: 0.265

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.268 AC: 40818 AN: 152034 Hom.: 6138 Cov.: 31 AF XY: 0.266 AC XY: 19805 AN XY: 74328

African (AFR) AF: 0.150 AC: 6207 AN: 41448

American (AMR) AF: 0.288 AC: 4395 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.396 AC: 1375 AN: 3472

East Asian (EAS) AF: 0.0438 AC: 227 AN: 5182

South Asian (SAS) AF: 0.267 AC: 1283 AN: 4806

European-Finnish (FIN) AF: 0.310 AC: 3272 AN: 10550

Middle Eastern (MID) AF: 0.238 AC: 70 AN: 294

European-Non Finnish (NFE) AF: 0.342 AC: 23243 AN: 67976

Other (OTH) AF: 0.263 AC: 555 AN: 2112

Alfa AF: 0.188 Hom.: 410

Bravo AF: 0.261

Asia WGS AF: 0.154 AC: 538 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	13
DANN	Benign	0.81
PhyloP100		-0.11
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2790098; hg19: chr6-45442450;